Ventromedial hypothalamic glucokinase is an important mediator of the counterregulatory response to insulin-induced hypoglycemia.

Published

Journal Article

OBJECTIVE: The counterregulatory response to insulin-induced hypoglycemia is mediated by the ventromedial hypothalamus (VMH), which contains specialized glucosensing neurons, many of which use glucokinase (GK) as the rate-limiting step in glucose's regulation of neuronal activity. Since conditions associated with increased VMH GK expression are associated with a blunted counterregulatory response, we tested the hypothesis that increasing VMH GK activity would similarly attenuate, while decreasing GK activity would enhance the counterregulatory response to insulin-induced hypoglycemia. RESEARCH DESIGN AND METHODS: The counterregulatory response to insulin-induced hypoglycemia was evaluated in Sprague-Dawley rats after bilateral VMH injections of 1) a GK activator drug (compound A) to increase VMH GK activity, 2) low-dose alloxan (4 mug) to acutely inhibit GK activity, 3) high-dose alloxan (24 microg), or 4) an adenovirus expressing GK short hairpin RNA (shRNA) to chronically reduce GK expression and activity. RESULTS: Compound A increased VMH GK activity sixfold in vitro and reduced the epinephrine, norepinephrine, and glucagon responses to insulin-induced hypoglycemia by 40-62% when injected into the VMH in vivo. On the other hand, acute and chronic reductions of VMH GK mRNA or activity had a lesser and more selective effect on increasing primarily the epinephrine response to insulin-induced hypoglycemia by 23-50%. CONCLUSIONS: These studies suggest that VMH GK activity is an important regulator of the counterregulatory response to insulin-induced hypoglycemia and that a drug that specifically inhibited the rise in hypothalamic GK activity after insulin-induced hypoglycemia might improve the dampened counterregulatory response seen in tightly controlled diabetic subjects.

Full Text

Duke Authors

Cited Authors

  • Levin, BE; Becker, TC; Eiki, J-I; Zhang, BB; Dunn-Meynell, AA

Published Date

  • May 2008

Published In

Volume / Issue

  • 57 / 5

Start / End Page

  • 1371 - 1379

PubMed ID

  • 18292346

Pubmed Central ID

  • 18292346

Electronic International Standard Serial Number (EISSN)

  • 1939-327X

International Standard Serial Number (ISSN)

  • 0012-1797

Digital Object Identifier (DOI)

  • 10.2337/db07-1755

Language

  • eng